KR20090080070A - Omega-3 fatty acids and dyslipidemic agent for reduction of apo-b levels - Google Patents

Abstract

Methods of utilizing a combined administration or a unit dosage of a combination of a dyslipidemic agent and omega-3 fatty acids for the reduction of apolipoprotein-B levels. The methods are especially useful in the treatment of patients with hypercholesterolemia, hypertriglyceridemia, mixed dyslipidemia, coronary heart disease (CHD), vascular disease, atherosclerotic disease and related conditions, and for the prevention or reduction of cardiovascular, cardiac, and vascular events.

Description

OMEGA-3 FATTY ACIDS AND DYSLIPIDEMIC AGENT FOR REDUCTION OF APO-B LEVELS}

The present invention claims priority to US Provisional Application No. 60 / 850,280, filed October 10, 2006, the entirety of which is incorporated herein by reference.

The present invention is directed to a method of using a single dose or unit dosage form of a combination of dyslipidemia and omega-3 fatty acids for reducing apolipoprotein-B levels. This method treats patients suffering from primary hypertriglyceridemia or hypercholesterolemia or complex dyslipidemia, coronary heart disease (CHD), vascular disease, atherosclerosis and related conditions, and prevention of cardiovascular and vascular events. And particularly useful for reduction.

In humans, cholesterol and triglycerides are present as part of lipoprotein complexes in the bloodstream and can be separated into ultra high density lipoprotein (HDL), medium density lipoprotein (IDL), low density lipoprotein (LDL) and ultra low density lipoprotein (VLDL) fractions through ultracentrifugation. Can be. Cholesterol and triglycerides are synthesized in the liver, incorporated into VLDL and secreted into the plasma. High levels of total cholesterol (total-C), LDL-C and apolipoprotein B (membrane complexes for apo-B, LDL-C and VLDL-C) promote human atherosclerosis, HDL-C and its transport complex Reduces the level of phosphorous apolipoprotein A (apo-A), which is associated with the progression of atherosclerosis. In addition, cardiovascular disease incidence and mortality in humans is proportional to the levels of TC and LDL-C and inversely proportional to the level of HDL-C. In addition, the researchers found that non-HDL cholesterol (non-HDL-C), determined by subtracting HDL-C from TC, is an important indicator of hypertriglyceridemia, vascular disease, atherosclerosis and related conditions. Non-HDL-C particles contain apo-B as membrane-composite apolipoproteins. Although non-HDL-C is a good measure of the total amount of cholesterol present in atherosclerotic apo-B-containing particles, direct measurement of apo-B may provide a better measure of the amount of atherosclerotic particles per unit serum. Can be.

Although LDL-C is a lipid level commonly used to assess cardiovascular risk, apo-B may better reflect lipid risk. See Sniderman, Am. J. Cardiol. 90 (suppl): 48i-54l (2002) describes evidence supporting apo-B levels in predicting coronary artery disease risk and that it is superior to the calculated LDL-C levels.

Cardiovascular disease (CVD) is a broad term that encompasses a variety of diseases and conditions. It refers to any disorder in any of the various parts of the cardiovascular system, including the heart and all blood vessels found throughout the body. Heart diseases may include coronary artery disease, CHD, cardiomyopathy, valve heart disease, pericardial disease, congenital heart disease (eg, narrowing, atrial or ventricular septal defect), and heart failure. Vascular diseases may include atherosclerosis, atherosclerosis, hypertension, stroke, vascular dementia, aneurysms, peripheral arterial disease, intermittent claudication, vasculitis, venous insufficiency, venous thrombosis, varicose veins and lymphedema. Some patients may receive treatment for their CVD (angioplasty with or without stents, or angioplasty), such as vascular or coronary angioplasty. Some types of cardiovascular disease are congenital, but many types are acquired, which can result from unhealthy habits such as sedentary lifestyle and smoking. Some types of CVD may also have additional heart problems, such as angina, major cardiovascular accidents (MACE) and / or major coronary accidents (MCE), such as myocardial infarction (MI) or coronary interventions, or even death (heart or cardiovascular). ), Which underscores the importance of efforts to treat and prevent CVD.

Primary prevention efforts are focused on reducing or preventing the progression of known risk factors for CVD with the aim of delaying or preventing the onset of CVD, MACE or MCE. Secondary preventive efforts focus on reducing recurrent CVD and reducing mortality, MACE or MCE in chronic CVD patients.

MACE includes cardiac death, other cardiovascular, MCE (myocardial infarction (MI) and coronary interventions such as coronary angioplasty, angioplasty, percutaneous coronary angioplasty (PTCA), percutaneous coronary intervention (PCI), and coronary artery). Bypass transplantation (CABG)), unstable angina, stroke, hospitalization for transient ischemic attack (TIA) and hospitalization for peripheral arterial disease (PAD) and / or intervention.

The Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, NIH Publication No. 02-5215 (September 2002) (also known as "NCEP ATP III") recommends cholesterol lowering therapy in an effort to reduce the risk of CHD. In ATP III, CHD is defined as symptomatic ischemic heart disease, including MI, stable or unstable angina, myocardial ischemia and coronary artery procedures as evidenced by nondestructive testing. ATP III, along with other lipids to be controlled, including triglycerides (TG), non-HDL-C and HDL-C, indicate that LDL-C is a major target of lipid therapy. apo-B has recently been listed as a risk factor. Although ATP III did not intend to replace LDL-C as a major target for lipid therapy, it was noted that limited epidemiological and clinical trial evidence supports that apo-B predominates over LDL-C in risk prediction.

The guiding principle of ATP III is that the efficacy of LDL-C lowering therapy modulates the individual's absolute risk for CHD. The risk assessment is divided into short-term (≤10 years) and long-term (> 10 years) risks for CHD, with LDL-C target values adjusted accordingly. In addition, ATP III defines three category risks for CHD that alter LDL-C targets: chronic CHD and CHD risk equivalents, multiple (2+) risk factors, and 0 to 1 risk factors. Chronic CHD and CHD risk equivalents include CHD, other clinical atherosclerosis, diabetes, multiple risk factors, and a 10 year risk for CHD> 20%. The main independent risk factors belonging to the risk factor coefficients include tobacco smoking, high blood pressure, low HDL-C, family history and age of premature CHD.

The LDL-C targets for the three risk factors are as follows.

Risk factor LDL-C target value CHD and CHD Risk Equivalents <100 mg / dl Multiple (2+) Risk Factors <130 mg / dl 0 to 1 risk factor <160 mg / dl

* The LDL-C target value for multiple risk factor humans with a 10 year risk of> 20% is <100 mg / dl.

ATP III also outlines the LDL-C target value for the patient based on the percentage of the 10-year risk for CHD.

10 year risk LDL-C target value > 20% <100 mg / dl 10 to 20% <130 mg / dl <10% and multiple (2+) risk factors <130 mg / dl <10% and 0-1 risk factors <160 mg / dl

Agents such as dyslipidemia and omega-3 fatty acids have generally been used to treat adult endogenous hyperlipidemia after myocardial infarction (MI), which belongs to the “cardiovascular accident” and in hypercholesterolemia and hypertriglyceridemia.

Dyslipidemic agents typically include HMG CoA reductase inhibitors (statins), cholesterol absorption inhibitors, niacin and derivatives such as nicotinamide, fibrate, bile acid adsorbents, MTP inhibitors, LXR agonists and / or antagonists, and PPAR agonists And / or antagonists.

Statins, which are 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, are for example used to treat hyperlipidemia and arteriosclerosis. Typically, statin monotherapy has been used to treat cholesterol levels, especially when the patient is not at an acceptable LDL-C level. Statins inhibit the enzyme HMG-CoA reductase, which controls the rate of cholesterol production in the body. Statins lower cholesterol by slowing cholesterol production and by increasing the liver's ability to eliminate LDL-cholesterol already present in the blood. Thus, the main effect of statins is to lower LDL-C levels. Statins have been shown to reduce the risk of CHD by about one third. However, statins only seem to have a modest effect on the TG-HDL axis. In addition, monotherapy with various statins is known to significantly reduce apo-B levels, for example from about 25 to about 40% from baseline. See, eg, Ballantyne et al., Am. Heart J. 151 (5): 975.e1-975.e9 (2006).

Cholesterol absorption inhibitors such as ezetimibe and MD-0727 are a class of lipid-lowering compounds that selectively inhibit intestinal absorption of cholesterol. Ezetimibe acts on the brush border of the small intestine to reduce the uptake of bile and food cholesterol into the intestinal cells from the small intestine. Results from a study presented at the 2006 World Cardiology Congress showed that the combination of ezetimibe and simvastatin had a superior effect than simvastatin alone at the apo-B level in patients with hypercholesterolemia. Orse et al., Effects Of Ezetimibe / simvastatin On Lipoprotein Subclasses In Patients With Primary Hypercholesterolemia, 2006 World Cardiology Congress-poster presentation], Ballantyne et al., Effects of Ezetimibe / simvastatin Compared to Simvastatin Monotherapy in Reducing C -Reactive Protein and Low Density Lipoprotein-Cholesterol, 2006 World Cardiology Congress-poster presentation.

Cholesteryl ester transfer protein (CETP) inhibitors, such as tocetrapib, specifically inhibit CETP molecules that move cholesterol from the HDL form to the LDL form. Thus, inhibiting this molecule is a promising approach to increase HDL cholesterol levels. It is reported that tocetrapib also reduces levels of LDL-C and apo-B, both when given as monotherapy and when administered with statins. Bhardwaj et al., Indian J. Pharmacol. 37:46 (2005).

Niacin (nicotinic acid or 3-pyridinecarboxylic acid) is already used to treat hyperlipidemia and atherosclerosis. Niacin is known to reduce total cholesterol, LDL-C and triglycerides and increase HDL-C. Niacin therapy is also known to reduce serum levels of apo-B. However, the magnitude of individual lipid and lipoprotein responses from niacin therapy may be affected by the severity and type of underlying lipid abnormalities. In one study, low doses of niacin and atorvastatin (20 mg) or rosuvastatin (10 mg) lowered apo-B levels comparable to ezetimibe-simvastatin combination or rosuvastatin alone. McKenney et al. Atherosclerosis 7 (suppl): 174. Abstract Tu-W27: 4 (2006).

Fibrates, such as fenofibrate, bezafibrate, clofibrate, and gemfibrozil, are PPAR-alpha agonists, and are given to patients to reduce triglyceride-rich lipoproteins, increase HDL, and reduce atheromatous LDL. Used. Fibrate is typically administered orally to such patients.

Fenofibrate or 2- [4- (4-chlorobenzoyl) phenoxy] -2-methyl-propanoic acid 1-methylethyl ester belonging to the fibrate family has been active for several years due to its efficacy in lowering blood triglycerides and cholesterol levels Known as a component. Fenofibrate is an active ingredient that is insoluble in water, so absorption of fenofibrate in the digestive tract is limited. Treatment with 40 to 300 mg of fenofibrate per day can reduce cholesterol levels by 20-25% and triglyceridemia by 40-50%.

Bile acid adsorbents such as cholestyramine, cholestipol, and coleseberam are a class of drugs that bind bile acids, preventing the digestive system from reabsorbing them, thereby reducing cholesterol levels. A common effect of bile acid adsorbents is to reduce LDL-cholesterol by about 10-20%. Small amounts of adsorbent can usefully reduce LDL-cholesterol. One study reports that combination treatment with fluvastatin and cholestyramine significantly reduces apo-B levels. Bard et al., Am. J. Cardiol., 76 (2): 65A-70A (2005).

MTP inhibitors, such as implitapide, are known to inhibit the secretion of cholesterol and triglycerides.

Liver X receptor (LXR) is a "cholesterol sensor" that regulates the expression of genes involved in lipid metabolism in response to certain oxysterol ligands (Repa et al., Annu. Rev. Cell Dev. Biol. 16: 459 -481 (2000)]. LXR agonists and antagonists are potential therapeutics for dyslipidemia and atherosclerosis.

PPAR-gamma agonists such as thiazolidinedione pioglitazone and rosiglitazone are known to improve cardiovascular risk and surrogate markers of atherosclerosis. For example, thiazolidinediones reduce C-reactive protein and carotid intima-media thickness. Non-thiazolidinediones such as Tesaglitasar, Nabiglithazar and Muraglitasar are dual alpha / gamma PPAR agonists. These compounds are used to lower glucose, insulin, triglycerides and free fatty acids. In one study, it has been shown to significantly lower apo-B levels of rosiglitazone. See Goldberg et al., Diabetes Care 28 (7): 1547-1554 (2005).

Partial PPAR-gamma agonists / antagonists such as metaglydacene are used for the treatment of type II diabetes.

Marine oil, also commonly referred to as fish oil, is a good source of two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have been shown to regulate lipid metabolism. . Omega-3 fatty acids have been shown to have beneficial effects on risk factors for cardiovascular disease, especially mild hypertension, hypertriglyceridemia and on the activity of coagulation factor VII phospholipid complexes. Omega-3 fatty acids lower serum triglycerides, raise serum HDL-cholesterol, lower systolic and diastolic blood pressure and pulse rate, and lower the activity of the blood coagulation factor VII phospholipid complex. In addition, omega-3 fatty acids appear to be widely tolerated without causing any serious side effects.

One form of omega-3 fatty acids is a concentrate of omega-3 long-chain polyunsaturated fatty acids from fish oils containing DHA and EPA, marketed under the trade name Omacor ^® , and now known as Lovaza ™. have. Omega-3 fatty acids in this form are described, for example, in US Pat. Nos. 5,502,077, 5,656,667 and 5,698,594, each of which is incorporated herein by reference.

Patients with complex dyslipidemia or hypercholesterolemia often have blood LDL cholesterol levels above 190 mg / dl, triglyceride levels above 200 mg / dl and apo-B levels above 0.9 g / l. In many patients with hypertriglyceridemia, hypercholesterolemia, and / or complex dyslipidemia, diet and mono-drug therapy always decrease adequately enough to reach target values for LDL cholesterol, triglycerides and / or apo-B levels It is not meant to be. In such patients, complementary combination therapy of dyslipidemia and omega-3 fatty acids may be desirable.

Many studies have investigated the combined effects of omega-3 fatty acids and statin therapy on apo-B levels. Most of these studies have found that statins significantly reduce apo-B levels, but most studies also report that it is not sufficient to add omega-3 fatty acid treatments to significantly reduce apo-B levels.

Hong et al. Studied the effects of fish oil and simvastatin in patients with coronary heart disease and complex dyslipidemia. Patients with baseline triglyceride levels of 292.8 mg / dl or 269.5 mg / dl were initially treated with simvastatin 10-20 mg / 1 day for 6-12 weeks. Patients were then treated with simvastatin and placebo, or simvastatin and fish oil (Meilekang ™) 3 g / 1 day. Combination treatment significantly reduced triglyceride levels when compared to baseline and placebo. In addition, the combination treatment numerically increased HDL-C levels and numerically decreased LDL-C levels when compared to baseline. However, changes in HDL-C levels and LDL-C levels were not statistically significant. Apo-B levels were increased in the combination treatment group, but apo-B levels were numerically decreased in the placebo group. Hong et al., Chin. Med. Sci. J. 19: 145-49 (2004).

Contacos et al. Studied the effects of fish oil and pravastatin in patients with complex hyperlipidemia. Patients with baseline triglyceride levels of 4.6 to 5.5 mmol / l (404 to 483 mg / dl) were treated with pravastatin 40 mg / 1 day, fish oil (Himega ™, 2: 1 ratio of EPA / DHA for 6 weeks). Initial treatment with 6 g / day, or placebo, containing 3 g of omega-3 fatty acid. All patients were then treated with pravastatin and fish oil for an additional 12 weeks. Initial treatment with pravastatin significantly reduced LDL-C levels. Combination treatment of pravastatin and fish oil also significantly reduced triglycerides and LDL-C levels. However, adding fish oil to pravastatin monotherapy resulted in only a numerical increase in LDL-C levels, which was not statistically significant. Treatment with fish oil alone significantly reduced triglyceride levels, but increased LDL-C levels. Compared to fish oil alone treatment (but not compared to baseline), the combination treatment for this group significantly reduced LDL-C levels. apo-B levels were significantly reduced with pravastatin treatment. Combination treatment with fish oil further reduced apo-B levels numerically, but this additional reduction was reported to be insignificant compared to pravastatin monotherapy. Contacos et al., Arterioscl. Thromb. 13: 1755-62 (1993).

Grekas et al. Reported a combination of low doses of pravastatin and fish oil in dyslipidemia after kidney transplantation. Thirty kidney transplant patients with persistent hypercholesterolemia (total cholesterol> 200 mg / dl) and receiving immunosuppressive therapy were given a standard diet for 4 weeks followed by 20 mg of pravastatin for 8 weeks. Baseline triglyceride levels at the diet stage were 184 mg / dl. This period was followed by a standard diet for an additional four weeks followed by eight weeks of therapy using 20 mg of pravastatin and 1 g of fish oil (prolipid). Baseline triglyceride levels at the diet stage were 169 mg / dl. Apo-B levels were not significantly reduced with diet + statin therapy. However, diet + statin + fish oil has been reported to significantly reduce apo-B levels. See Grekas et al., Nephron (2001) 88: 329-333. The findings of Grekas et al. Seem suspicious in that the study did not show a significant reduction in apo-B levels using pravastatin therapy alone. Plastic Barcol (PRAVACHOL), ^® (pravastatin) is referred to as primary and additives in the diet for reducing the level of apo-B rising in patients with dyslipidemia or more cholesterol and compound. Thus, the fact that the study of grekas et al. Did not show a significant apo-B reduction when using pravastatin doubts the findings.

Huff et al. Found that a combination of dietary fish oil and lovastatin reduced apo-B levels in both the ultra low density lipoprotein (VLDL) and low density lipoprotein (LDL) portions of mini pigs. However, this study only compared the combination treatment versus fish oil monotherapy, not the combination treatment versus statin monotherapy. See Huff et al., Arteroscl. Thromb., 12 (8): 901-910 (August 1992).

Jula et al. Studied the effects of diet and simvastatin on various serum lipids in patients with hypercholesterolemia. After the open placebo period, subjects were divided into "habitual diet" or "dietary treatment" groups. The dietary treatment consisted of a Mediterranean-type diet, which provides up to 10% of energy from saturated and trans-saturated fatty acids, with cholesterol intakes of up to 250 mg / 1 day, of plant and seafood origin. Omega-3 fatty acid intake is more than 4 g / 1 day, the ratio of omega-6 fatty acids to omega-3 fatty acids is less than 4, and the intake of fruits, vegetables and soluble fiber is increased. Subsequently, they were also classified as subjects receiving simvastatin 20 mg / 1 day or plasma for 12 weeks in a double blind crossover mode. Subjects in the diet treatment group and simvastatin group had a significant decrease in apo-B levels. The interaction between the two variables was reported as significant. See Jula et al., JAMA 287 (5): 598-605 (2002).

US Patent Application Publication No. 2003/0170643 discloses apo-B and / or apo-B containing lipoproteins and / or atherosclerosis by stimulating post-ER pre-secretory proteolysis (PERPP). A method of treating a patient by administering a therapeutic agent that lowers the plasma concentration of the forming lipoprotein component.

The effects of statins and omacor ^® omega-3 fatty acids have been studied. For example, Hansen (Hansen) and the like were investigated the effects of omega-3 fatty acids Omar cor ^® 6 g / 1 day the combination lovastatin (40 mg / 1 days) in patients with hypercholesterolemia. Patients with baseline triglyceride levels of 1.66 mmol / l (about 146 mg / dl) were treated with Omakor ^® 6 g / 1 day for 6 weeks, followed by 40 mg / 1 day lovastatin for an additional 6 weeks, and last Treatment was with a combination of omakor ^® and lovastatin for 6 weeks. Lovastatin monotherapy significantly increased HDL-C levels and significantly reduced triglyceride and LDL-C levels. After combination treatment, triglyceride and LDL-C levels were significantly reduced. Apo-B levels were significantly reduced with lovastatin monotherapy and more numerically reduced with the addition of omega-3 fatty acids, but this additional decrease did not appear to be significant compared to lovastatin monotherapy. Hansen et al., Arterioscl. Thromb. 14 (2): 223-229 (February 1994).

Nordoy et al. Studied the effects of atorvastatin and omega-3 fatty acids on patients with hyperlipidemia. Patients with baseline triglyceride levels of 3.84 mmol / l (about 337 mg / dl) or 4.22 mmol / l (about 371 mg / dl) were treated with atorvastatin 10 mg / 1 day for 5 weeks. It was then supplement for an additional 5 weeks of Omaha cor ^® 2 g / atorvastatin treatment on a daily or placebo. Atorvastatin monotherapy significantly increased HDL-C levels compared to baseline and significantly reduced triglycerides, LDL-C and apo-B levels. Combination treatment further increased HDL-C levels compared to atorvastatin alone. Triglyceride, LDL-C and apo-B levels were numerically slightly reduced compared to atorvastatin monotherapy when combined treatment was used, but this decrease was not significant. Nordoy et al., Nutr. Metab. Cardiovasc. Dis. (2001) 11: 7-16.

Chan (Chan) and the like fasting (fasted state) from, more than atorvastatin (40 mg / 1 day) and 4 Omar cor ^® combination treatment of 4 g / 1 about a s insulin resistance patients with hypertriglyceridemia obesity Was studied. Patients with baseline triglyceride levels of 1.7 to 2.0 mmol / l (about 150 to 170 mg / dl) were treated with atorvastatin 40 mg / 1 day and placebo for 6 weeks; Omarcor ^® 4 g / 1 day and placebo; Atorvastatin combination of a statin and Omar cor ^®; Or a combination of placebos. Atorvastatin monotherapy significantly reduced apo-B levels. Combination treatment also significantly reduced apo-B levels compared to the placebo group. However, the effects resulting from Omar cor ^® was not significant. See Chan et al., Diabetes, 51: 2377-2386 (Aug. 2002).

Nord Deutscher et al studied the efficacy of familial hypercholesterolemia, but (as recognized as "K-85") cardiovascular diseases patients lovastatin 40 mg / 1 at free and Omar Cordon ^® 6 g / 1 days combination treatment . The study included three intervention sessions, each six weeks apart from a six week washout period. The final trial was done 12 weeks after the last intervention. Apo-B levels decreased numerically slightly with omega-3 fatty acid monotherapy and significantly decreased with lovastatin monotherapy. Combination treatment also significantly reduced apo-B levels relative to baseline. However, this reduction did not appear to be significant as compared to lovastatin monotherapy. Nordoy et al., Essent. Fatty Acids Eicosanoids, Invited Pap. Int'l Congr. 4 ^th , 256-61 (1998).

Nordoi et al. Also studied the efficacy and safety of simvastatin and omega-3 fatty acid treatments in patients with hyperlipidemia. Patients with baseline triglyceride levels of 2.76 mmol / l (about 243 mg / dl) or 3.03 mmol / l (about 266 mg / dl) were treated with simvastatin 20 mg / 1 day or placebo for 5 weeks, followed by all patients Treatment with simvastatin 20 mg / 1 day for an additional 5 weeks. The patient was then further treated with Omakor ^® 4 g / 1 day or placebo for an additional 5 weeks. Administration of omega-3 fatty acids and simvastatin moderately reduced total cholesterol in serum, decreased triglycerol levels, and slightly decreased apo-B levels numerically. However, the effect attributable to omega-3 fatty acids was not significant. See Nordoy et al., J. of Internal Medicine, 243: 163-170 (1998).

Durrington et al. Tested the efficacy, stability and tolerance of the combination of omacor ^® omega-3 acid and simvastatin in patients with chronic coronary heart disease and persistent hypertriglyceridemia. The average baseline triglyceride levels of 2.3 mmol / l patient in excess of the (average patient serum triglyceride level was 4.6 mmol / l Im) for simvastatin 10 to 40 mg / 1 day, and Omar cor ^® 2 g / 24 weeks to 1 day or placebo Was treated with a double-blind trial, after which both groups were awarded Omakor ^® in an open study for an additional 24 weeks. Combination treatment significantly reduced triglyceride levels within 12 weeks compared to baseline monotherapy. In addition, VLDL cholesterol levels were reduced by 30-40% in these patients. Numerical (not statistically significant) decreases occurred at 12 and 48 weeks, but LDL-C levels decreased significantly compared to baseline monotherapy only after 48 weeks. The addition of omega-3 fatty acids to simvastatin monotherapy resulted in a slight numerical (statistically insignificant) decrease in apo-B levels. See Durrington et al., Heart, 85: 544-548 (2001).

<Overview of invention>

There is a need in the art for methods of increasing apo-B levels reduction compared to monotherapy with dyslipidemia alone. This method can be used to treat hypercholesterolemia, hypertriglyceridemia, complex dyslipidemia, coronary heart disease (CHD), vascular disease, atherosclerosis and related conditions in a subject, such as a human subject, and / or cardiovascular and / or It is particularly useful for the prevention or reduction of vascular accidents.

Some embodiments of the present invention provide a method of utilizing a combination of dyslipidemia and omega-3 fatty acids to reduce apo-B levels, the method comprising hypercholesterolemia, hypertriglyceridemia, complex dyslipidemia , Coronary heart disease, vascular disease, atherosclerosis and related conditions, and / or prevention or reduction of cardiovascular and vascular accidents.

Some embodiments according to the present invention comprise reducing apo-B levels in a subject as compared to treating the dyslipidemia alone by administering to the subject a therapeutically effective amount of the dyslipidemic agent and the omega-3 fatty acid. Provides blood lipid therapy in

In another embodiment, the present invention provides a subject group and the dyslipidemia agent by administering to the subject group a combination of an omega-3 fatty acid and an effective amount of a dyslipidemic agent to reduce apo-B levels in the subject group Reducing the apo-B levels of the subject group as compared to treating the alone. In a preferred embodiment, the subject group has a condition of at least one of hypertriglyceridemia, hypercholesterolemia, complex dyslipidemia, vascular disease and / or atherosclerosis and related conditions.

In a further embodiment, the dyslipidemic and omega-3 fatty acids are administered as a single pharmaceutical composition as a combination product, such as a unit dosage form comprising the dyslipidemic and omega-3 fatty acids.

In a preferred embodiment, the pharmaceutical composition (s) comprise lovaza ™ omega-3 fatty acids as described in US Pat. Nos. 5,502,077, 5,656,667 and 5,698,594. In another preferred embodiment, the pharmaceutical composition (s) comprises omega-3 fatty acids present at a concentration of at least 40% by weight relative to the total fatty acid content of the composition (s).

In another preferred embodiment, the omega-3 fatty acids comprise at least 50% by weight EPA and DHA compared to the total fatty acid content of the composition, wherein the EPA and DHA have a weight ratio of EPA: DHA of 99: 1 to 1:99, Preferably 1: 2 to 2: 1.

In an embodiment of the invention, the dyslipidemic agent is a statin, including but not limited to pitavastatin, simvastatin, rosuvastatin, pravastatin, atorvastatin, lovastatin and fluvastatin. In a preferred embodiment, the statin used in combination with omega-3 fatty acids is simvastatin.

In one aspect of the invention, the combination product is used for the treatment of patients with primary hypertriglyceridemia or hypercholesterolemia or complex dyslipidemia.

In a further preferred embodiment of the invention, the triglyceride level in the serum of the patient (or group of subjects) prior to the first administration of the combination of the dyslipidemic agent and the omega-3 fatty acid, ie at baseline, is from about 200 to about 499 mg / dl.

The present invention also includes the use of effective amounts of dyslipidemia and omega-3 fatty acids for the manufacture of a medicament useful for any of the methods of treatment mentioned herein.

Other features and advantages of the invention will be apparent to those skilled in the art upon review of the following or on practice of the invention.

The present invention relates to the use of dyslipidemia and omega-3 fatty acids to reduce apo-B levels beyond those obtained by treating dyslipidemia alone. The method of the present invention is directed to the treatment of primary hypertriglyceridemia or hypercholesterolemia or complex dyslipidemia, coronary heart disease, vascular disease, atherosclerosis and related conditions, and / or prevention or reduction of cardiovascular and / or vascular accidents. Especially useful. In a preferred embodiment, the subject's baseline apo-B level is greater than 0.9 g / l, and using the present invention, the apo-B level is reduced to less than 0.9 g / l.

In some embodiments, the subject has a non-HDL-C level of at least 130 mg / dl, more preferably at least 160 mg / dl, and using the present invention, apo-B levels are relative to baseline and / or dyslipidemia. It is preferably reduced by 2% or more than treatment of the blood alone.

In some embodiments, the subject has elevated LDL-C levels (eg, at least 100 mg / dl, at least 100 mg / dl to less than 130 mg / dl, at least 130 mg / dl, or at least 160 mg / dl) and And / or have elevated triglyceride levels (eg, at least 150 mg / dl, at least 200 mg / dl, 200 to 499 mg / dl, or at least 500 mg / dl), in both cases as complex dyslipidemic subjects. Can be considered.

In some embodiments, the present invention provides novel combinations. In a preferred embodiment, the combination is an omega-3 fatty acid and dyslipidemic agent, in which omega-3 fatty acids are administered simultaneously with the administration of the dyslipidemia agent, for example as a single fixed dose pharmaceutical composition or as a separate composition administered simultaneously. It includes.

In another preferred embodiment, the administration comprises the omega-3 fatty acid and the dyslipidemic agent, wherein the omega-3 fatty acid is administered separately from the dyslipidemic agent but in a concurrent treatment regimen. For example, dyslipidemia may be administered once per day and omega-3 fatty acids may be administered twice per day. Those skilled in the art having the benefit of the present invention will know that the precise dosage and schedule of administration of omega-3 fatty acids and dyslipidemic agents will vary depending on a number of factors, including the route of administration, severity of the condition, coexisting diseases and the use of other agents. I will understand that.

In some embodiments, the claimed method of administration is first-line therapy, which means a first type of treatment defined for a condition or disease. In other embodiments, the claimed method of administration is a second prescription, which is due to, for example, initial treatment (primary prescription, eg dyslipidemia or Treatment with omega-3 fatty acids alone) does not work or become inappropriate for the therapeutic target.

In some embodiments, the present invention is suitable for primary prevention. In other embodiments, the present invention is suitable for secondary prevention.

In a preferred embodiment, the selected group of subjects are awarded dyslipidemia therapy before combination therapy of dyslipidemia and omega-3 fatty acids. Other active agents (other than omega-3 fatty acids) can also be used prior to combination therapy of dyslipidemia and omega-3 fatty acids.

In a preferred embodiment, the invention comprises administering to the subject group an effective amount of dyslipidemia and omega-3 fatty acid, wherein the triglyceride level and apo-B level of the subject group after administration to the subject group Blood lipid therapy in the subject group, which is reduced compared to the control group treated alone and the HDL-C level of the subject group is increased compared to the control group treated with dyslipidemia alone and / or relative to baseline. do. Baseline triglyceride levels in the subject group are preferably 200 to 499 mg / dl.

In another preferred embodiment, the invention comprises administering to the subject group an effective amount of dyslipidemia and omega-3 fatty acids, wherein LDL-C is not increased by more than 1% relative to the baseline after administration to the subject group. Triglyceride levels and apo-B levels in the subject group are reduced compared to the control group treated with dyslipidemia alone without blood lipid therapy in the subject group. Baseline triglyceride levels in the subject group are preferably 200 to 499 mg / dl.

In another preferred embodiment, the invention comprises administering to the subject group an effective amount of dyslipidemia and omega-3 fatty acids, wherein LDL-C is not increased by more than 1% relative to the baseline after administration to the subject group. Non-HDL-C levels, total cholesterol levels, triglyceride levels and apo-B levels in the subject group were reduced compared to the control group treated with dyslipidemia alone, and the HDL-C level in the subject group was dyslipidemia. Blood lipid therapy in a group of subjects, compared to a control group treated with agents alone.

In another preferred embodiment, the invention comprises administering to the subject group an effective amount of a dyslipidemic agent and an omega-3 fatty acid, wherein the non-HDL-C level of the subject group is administered to the subject group after the Blood lipid therapy in a group of subjects, which is reduced compared to a control group treated alone. The subject group preferably has a baseline triglyceride level of 200 to 499 mg / dl.

In another preferred embodiment, the present invention provides a group of subjects, and by administering to the subject group a combination of a dyslipidemic agent and an omega-3 fatty acid in an amount effective to reduce triglyceride levels and apo-B levels of the subject group Subject group without increasing LDL-C levels, including decreasing triglyceride levels and apo-B levels in the subject group compared to treatment with the HMG-CoA reductase inhibitor alone without increasing LDL-C levels Methods for reducing triglyceride levels and apo-B levels in

The phrase “compared to treatment with dyslipidemia alone” refers to treatment of the same subject or group of subjects, or comparable subjects or groups of subjects (ie, specific blood proteins or lipids such as cholesterol or triglyceride levels in different treatment groups). In relation to the treatment of the subject (s) within the same class). The terms "decrease" and "increase" associated with the method of an embodiment have a general and usual meaning (ie, a probability of 5% or less (p = 0.05 or less), more preferably 2.5% or less (p = 0.025 or less). It is intended to mean a statistically significant decrease or increase accordingly. In some embodiments of the invention, the dyslipidemia alone statistically significantly reduces or increases (eg, decreases apo-B levels) and combination therapy of dyslipidemia and omega-3 fatty acids Decreases or increases this level statistically more significantly.

In addition to reducing apo-B levels, the methods and compositions of the present invention also provide for any lipid level of a treated subject or group of subjects, ie non-HDL-C levels, triglycerides, compared to treatment with dyslipidemia alone. It can be used to reduce levels, VLDL-C levels, total C levels, RLP-C levels, Lp-PLA2 levels and / or apo-C3 levels. In addition, the methods and compositions of the present invention can be used to increase HDL-C levels compared to treatment with dyslipidemia alone. Preferably, the methods and compositions of the present invention can be used without increasing LDL-C levels relative to baseline.

Preferably, the non-HDL-C levels may be reduced by at least about 5%, preferably at least about 7%, from the baseline and / or at least about 5%, preferably, than treated with dyslipidemia alone. Can be further reduced by at least about 7%.

Preferably, triglyceride levels may be reduced by at least about 20%, preferably at least about 25%, relative to the baseline, and / or at least about 10%, preferably at least about 15, compared to treatment with dyslipidemic agents alone. % Or more, more preferably about 20% or more.

Preferably, VLDL-C levels may be reduced by at least about 15%, preferably at least about 20%, more preferably at least about 25% relative to the baseline and / or treated with dyslipidemic agents alone By at least about 10%, preferably at least about 15%, more preferably at least about 20%.

Preferably, the total C level may be reduced by at least about 3%, preferably at least about 5% relative to the baseline and / or at least about 2%, preferably at least about, treatment with dyslipidemia alone. By 3% or more.

Preferably, the RLP-C level may be reduced by at least about 15%, preferably at least about 20%, more preferably at least about 25% relative to the baseline and / or treated with dyslipidemia alone By at least about 10%, preferably at least about 15%, more preferably at least about 20%.

Preferably, Lp-PLA2 levels may be reduced by at least about 5%, preferably at least about 7%, more preferably at least about 10% relative to the baseline and / or treated with dyslipidemic agents alone By at least about 3%, preferably at least about 5%, more preferably at least about 7%.

Preferably, the apo-B level may be reduced by at least about 3%, preferably at least about 4% relative to the baseline and / or at least about 1%, preferably at least, treated with dyslipidemia alone. By about 2% or more.

Preferably, apo-C3 levels may be reduced by at least about 5%, preferably at least about 7% relative to the baseline and / or at least about 8%, preferably at least, treated with dyslipidemia alone. By about 10% or more.

Preferably, HDL-C levels may be reduced by at least about 2%, preferably at least about 3%, relative to the baseline and / or at least about 3%, preferably at least, with dyslipidemia alone. By about 5% or more.

Preferably, the present invention also preferably reduces the total cholesterol ratio to HDL-C by at least about 5%, more preferably at least about 10% relative to the baseline and / or treats dyslipidemic agents alone About 5% or more, preferably about 10% or more.

The present invention can include dyslipidemias, now known or later known, in amounts that are generally recognized as safe. Preferred dyslipidemic agents include, but are not limited to, HMG CoA reductase inhibitors, including statins, cholesterol absorption inhibitors such as but not limited to ezetimibe, niacin and derivatives such as nicotinamide, CETP inhibitors such as tocetrapib Fibrate, such as fenofibrate, bezafibrate, clofibrate and gemfibrozil, but not limited to, bile acid adsorbents such as cholestyramine, cholestipol and coleseberam (but not limited to), MTP inhibitors, such as PCT Application Publication No. WO 00/38725, incorporated herein by reference, and Science, 282, 23 October 1998, pp. 751-754, including but not limited to, LXR agonists and / or antagonists, and PPAR agonists and antagonists (eg, PPAR-alpha, PPAR-gamma, PPAR-delta, PPAR-alpha / gamma, PPAR Gamma / delta, PPAR-alpha / delta, and PPAR-alpha / gamma / delta agonists, antagonists and partial agonists and / or antagonists), such as thiazolidinedione, non-thiazoli Dindione and metaglydacene, including but not limited to. There are six statins currently widely available, namely atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin and simvastatin. The seventh statin, pitavastatin, is in clinical trials. The eighth statin, cerivastatin, has recently been withdrawn from the US market. However, one of ordinary skill in the art will recognize that cerivastatin may be used in connection with some embodiments of the present invention once it is determined that cerivastatin is finally safe and effective.

In general, the effect of dyslipidemia is dose dependent, i.e., as the dose is increased, the therapeutic effect is increased. However, the effects of each dyslipidemic agent are different, so the level of therapeutic effect of a particular dyslipidemic agent may not necessarily be directly related to the level of the therapeutic effect of another dyslipidemic agent. However, one of ordinary skill in the art would know the correct dose to provide to a particular patient based on the severity and experience of the condition.

The term "omega-3 fatty acid" as used herein refers to natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates thereof (e.g., Zalaga, each of which is incorporated herein by reference US Patent Application Publication No. 2004/0254357 to Zaloga et al., And US Pat. No. 6,245,811 to Horrobin et al., Precursors or salts, and mixtures thereof. Examples of omega-3 fatty acid oils include omega-3 polyunsaturated long chain fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and α-linolenic acid; Esters of omega-3 fatty acids with glycerol, such as mono-, di- and triglycerides; And esters of omega-3 fatty acids with primary, secondary or tertiary alcohols such as fatty acid methyl esters and fatty acid ethyl esters. Preferred omega-3 fatty acid oils are long chain fatty acids such as EPA or DHA, triglycerides thereof, ethyl esters thereof and mixtures thereof. Omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof can be used in their pure form or as components of oils such as fish oil, preferably refined fish oil concentrates. Examples of commercial omega-3 fatty acids suitable for use in the present invention include Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International, P.C., Yorkshire, UK). International PLC)), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE (Pronova Biocare as., 1327 Lisaker, Norway).

Preferred compositions include the omega-3 fatty acids mentioned in US Pat. Nos. 5,502,077, 5,656,667 and 5,698,694, which are incorporated herein by reference in their entirety.

Another preferred composition is at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, even more preferably at least 70% by weight, most preferably at least 80% by weight, even 90% by weight. Omega-3 fatty acids present at a concentration of at least%. Preferably, the omega-3 fatty acids are at least 50% by weight, more preferably at least 60% by weight, even more preferably at least 70% by weight, most preferably at least 80%, such as about 84% by weight of EPA and DHA. It includes. Preferably, the omega-3 fatty acid is about 5 to about 100 weight percent, more preferably about 25 to about 75 weight percent, even more preferably about 40 to about 55 weight percent, most preferably about 46 weight percent Contains EPA. Preferably, the omega-3 fatty acid is about 5 to about 100 weight percent, more preferably about 25 to about 75 weight percent, even more preferably about 30 to about 60 weight percent, most preferably about 38 weight percent Contains DHA. Unless otherwise indicated, all of these percentages are based on weight relative to total fatty acid content in the composition. Although other forms may be used according to the invention, the weight percentages are preferably based on the ethyl ester form of the omega-3 fatty acid, but may be based on the free acid or ester form.

The EPA: DHA ratio may be 99: 1 to 1:99, preferably 4: 1 to 1: 4, more preferably 3: 1 to 1: 3, most preferably 2: 1 to 1: 2. . Omega-3 fatty acids may include pure EPA or pure DHA.

Omega-3 fatty acid compositions optionally include chemical antioxidants such as alpha tocopherol, oils such as soybean oil and partially cured vegetable oils and lubricants such as fractionated palm oil, lecithin and mixtures thereof.

The most preferred form of omega-3 fatty acid is lovaza ™ omega-3 acid (K85EE, Pronova Biocare A., Lisa, Norway) and preferably comprises the following features (per dosage form):

exam Minimum value Value Eicosapentaenoic acid C20: 5 430 mg / g 495 mg / g Docosahexaenoic Acid C22: 6 347 mg / g 403 mg / g EPA and DHA 800 mg / g 880 mg / g Total n-3 fatty acids 90% (w / w)

Combination products of dyslipidemia and concentrated omega-3 fatty acids may be dispersed in capsules, tablets, beverages, or in other solid oral dosage forms, liquid, soft gel capsules, coated soft gel capsules (see herein for reference). US Patent Application No. 11 / 716,020, cited) or other convenient dosage forms known in the art, such as oral liquids in capsules. In some embodiments, the capsule comprises hard gelatin. The combination product may also be contained in a liquid phase suitable for injection or infusion. The active ingredient of the present invention may also be administered in combination with one or more inactive pharmaceutical ingredients (also generally referred to as "excipients"). Inactive ingredients are formed, suspended, thickened, diluted, emulsified, stabilized, preserved, protected, colored, for example, with the appropriate and potent formulations acceptable, safe, convenient and acceptable for use. And flavor and dissolve.

Excipients include surfactants such as propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long chain fatty acids, polyethoxylated castor oil, glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, propylene glycol dicapryl Latex / dicaprate, polyethylene-polypropylene glycol copolymers, and polyoxyethylene sorbitan monooleate, cosolvents such as ethanol, glycerol, polyethylene glycol and propylene glycol, and oils such as palm oil, olive oil or safflower oil. The use of surfactants, cosolvents, oils or combinations thereof is generally known in the pharmaceutical arts, and as will be appreciated by those skilled in the art, any suitable surfactant may be used in connection with the present invention and embodiments thereof.

Concentrated omega-3 fatty acids may be administered daily in an amount of about 0.1 g to about 10 g, more preferably about 1 g to about 8 g, most preferably about 2 g to about 6 g. In one embodiment, the omega-3 fatty acid is administered in an amount up to 4 g / 1 day.

Dyslipidemias can be administered in amounts greater than, equal to, or less than a conventional full-strength dose as a single dose product. For example, dyslipidemia can be administered as a single dose product in an amount of from 10 to 100%, preferably from about 25 to 100%, most preferably from about 50 to 80% of the usual maximum drug dose. In one embodiment of the invention, the dyslipidemic agent is an HMG-CoA reductase inhibitor, or statin, which is generally from about 0.5 mg to 80 mg, more preferably from about 1 mg to about 1 gram of omega-3 fatty acid 40 mg, most preferably from about 5 mg to about 20 mg. The daily dose may range from about 2 mg to about 320 mg, preferably from about 4 mg to about 160 mg.

In some embodiments of the invention, the combination of dyslipidemia and omega-3 fatty acids is formulated in a single dosage or unit dosage form. In a preferred embodiment, the dyslipidemic agent is a statin selected from pitavastatin, atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin and simvastatin.

Bristol, located in Princeton, New Jersey - are manufactured in Myers Squibb (Bristol-Myers Squibb) Pravastatin is known in the market as infrastructure Barcol (Pravochol) ^® is hydrophilic. Pravastatin is best absorbed in the absence of food, ie on an empty stomach. The dose of pravastatin in the co-administration of concentrated omega-3 fatty acids is preferably 2.5 to 80 mg, preferably 5 to 60, more preferably 10 to 40 mg relative to the dose of concentrated omega-3 fatty acids. In one embodiment, the combination product using pravastatin is taken at or near bedtime, for example at 10 pm.

Lovastatin, marketed under the tradename Mevacor ^® by Merck, Whitehouse Station, NJ, is hydrophobic. Unlike pravastatin, lovastatin must be taken with food, so in some embodiments a combination product of concentrated omega-3 fatty acids and lovastatin should be taken with food. The dose of lovastatin in the co-administration of concentrated omega-3 fatty acids is preferably 2.5 to 100 mg, preferably 5 to 80 mg, more preferably 10 to 40 mg relative to the dose of concentrated omega-3 fatty acids.

Simvastatin, marketed under the trade name Zocor® at Merck, Whitehouse, NJ, is hydrophobic. The dose of simvastatin in the combined administration of concentrated omega-3 fatty acids is preferably 1 to 80 mg / 1 day, preferably 2 to 60 mg, more preferably 5 to 40 mg relative to the dose of concentrated omega-3 fatty acids. .

Atorvastatin sold under the trade name Lipitor Le (Lipitor) ^® in a pie-party (Pfizer) in the U.S., New York, NY is hydrophobic, is known as a synthetic statin. The dose of atorvastatin in the co-administration of concentrated omega-3 fatty acids is preferably 2.5 to 100 mg, preferably 5 to 80 mg, more preferably 10 to 40 mg relative to the dose of concentrated omega-3 fatty acids.

Fluvastatin, marketed under the trade name Lescol ^® by Novartis, New York, NY, is hydrophilic and known as synthetic statins. The dose of fluvastatin in the co-administration of concentrated omega-3 fatty acids is 5 to 160 mg, preferably 10 to 120 mg, more preferably 20 to 80 mg relative to the dose of concentrated omega-3 fatty acids.

Rosuvastatin is marketed under the trade name Crestor ^® from Astra Zeneca, Wilmington, Delaware. The dose of rosuvastatin in the co-administration of concentrated omega-3 fatty acids is 1 to 80 mg, preferably 2 to 60 mg, more preferably 5 to 40 mg relative to the dose of concentrated omega-3 fatty acids.

The daily doses of dyslipidemia and concentrated omega-3 fatty acids may be administered in 1 to 10 doses, preferably 1 to 4 times a day, most preferably 1 to 2 times a day. Other dosage forms may be used which provide unit dosage forms of dyslipidemia and concentrated omega-3 fatty acids, but administration is preferably oral administration.

In some embodiments, the formulations of the present invention may improve the effectiveness of one or both of each active ingredient administered as a conventional maximum medicament dose as compared to formulations of the prior art. In other embodiments, the formulations of the present invention can reduce the dose of dyslipidemia and / or omega-3 fatty acids as compared to formulations of the prior art while maintaining or even increasing the effectiveness of each active ingredient.

Combinations of the dyslipidemias and concentrated omega-3 fatty acids of the present invention may provide effects that are superior to any expected combined or additive effect of the two drugs alone. In addition, the combined or additive effect of the two drugs may depend on the initial triglyceride levels in the subject's blood. For example, if the triglyceride level of the subject is generally less than 150 mg / dL, it is normal, if it is within about 150 to 199 mg / dL, it is high, if it is about 200 to 499 mg / dL, it is high, and if it is 500 mg / dL or more Very high. The present invention can be used to lower "very high" triglyceride levels to "high" or "high" within less than 48 weeks, preferably within 24 weeks, more preferably within 12 weeks, and most preferably within 8 weeks. have.

The present invention may also be used to lower "high" triglyceride levels to "high" or "normal" in less than 48 weeks, preferably within 24 weeks, more preferably within 12 weeks, most preferably within 8 weeks. have.

Clinical Trial: Randomized Double-Blind Placebo Control Trial to Assess the Efficacy and Safety of Combination Therapy of Lovaza ™ and Simvastatin in Hypertriglyceridemic Subjects

Rover and Now triglycerides in patients with hypertriglyceridemia ™ Omega-3 fatty acids were performed and simvastatin (Joe Cortez ^®) randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of the combination treatment using the. Patients were initially treated with simvastatin 40 mg / 1 day for at least 8 weeks, after which baseline was measured. If baseline triglyceride levels were above normal (≧ 150 mg / dl) and the patient's LDL-C exceeded the NCEP ATP III target of 10% or less, it was appropriate for enrollment and randomization as patients. A total of 259 patients were randomized and received one or more lovaza ™ omega-3 fatty acids or placebo, with baseline triglyceride levels of 229 of these patients being between 200 and 499 mg / dl. After the initial treatment, statin therapy was continued in a double-blind manner, with an additional treatment for 4 weeks per day or placebo with lovaza ™ omega-3 fatty acids or placebo. The test was completed with 243 patients.

Table 1 below shows the results obtained for changes in various lipid and inflammatory parameters and indicators.

Tables 2 and 3 below show the rate of achievement of LDL-C target values recognized in the study above for Rovaza ™ treatment and placebo, respectively.

A more detailed analysis of apo-B reduction as a function of baseline LDL-C and non-HDL-C levels is provided by Lovaza ™, which reduces apo-B levels at elevated LDL-C and non-HDL-C baseline levels. The capacity of the treatment was significant and increased, demonstrating that placebo treatment changes apo-B levels randomly and not significantly.

Tables 4A, 4B and 5 below show apo-B reduction and other lipid parameter changes when using lovaza ™ treatment or placebo treatment for certain LDL-C and non-HDL-C patient subgroups. At higher LDL-C (≥100 mg / dL) and non-HDL-C (≥130 mg / dL) basal levels, lovaza ™ reduced apo-B, but at lower basal levels, Apo-B changes were not significant compared to placebo. Table 4B shows that the apo-B reduction effect is much more evident at higher LDL-C baseline levels, which appeared to involve a decrease in LDL-C levels.

Table 6 below shows apo-B reduction and other lipid parameter changes when using lovaza ™ or placebo treatment for patients with triglyceride baseline levels above 200 mg / dL versus patients below 200 mg / dL. At higher triglyceride baseline levels (≧ 200 mg / dL), lovaza ™ reduced apo-B, but the change in apo-B by lovaza ™ at lower baseline triglyceride levels was not significant compared to placebo.

Tables 7 and 8 show apo-B reduction and other lipid parameter changes when using lovaza ™ or placebo treatment for certain LDL-C / triglyceride and non-HDL-C / triglyceride patient subgroups. At higher LDL-C (≥100 mg / dL) basal levels and triglycerides (≥200 mg / dL) basal levels, and at higher non-HDL-C (≥130 mg / dL) basal levels and triglycerides ( ≧ 200 mg / dL) lovaza ™ reduced apo-B at baseline levels, but the change in apo-B by lovaza ™ at lower baseline levels was not significant compared to placebo.

All documents mentioned herein are incorporated herein by reference in their entirety.

Claims (22)

Compared to treating dyslipidemia alone by providing a subject group and administering to the subject group an amount of a combination of dyslipidemia and an omega-3 fatty acid effective to reduce apo-B levels in the subject group A method of reducing apo-B levels in a group of subjects, comprising reducing apo-B levels in a group. The method of claim 1, wherein the dyslipidemic agent is an HMG CoA reductase inhibitor, cholesterol absorption inhibitor, CETP inhibitor, niacin and derivatives, fibrate, bile acid adsorbent, MTP inhibitor, LXR agonist and / or antagonist, and PPAR agonist, Antagonist and / or partial agonist / antagonist. The method of claim 1, wherein the subject group has at least one of the conditions or diseases of hypertriglyceridemia, hypercholesterolemia, complex dyslipidemia, vascular disease, and atherosclerosis. The method of claim 1, wherein the LDL-cholesterol level of the subject group is at least 100 mg / dL. The method of claim 1, wherein the LDL-cholesterol level of the subject group is at least 100 mg / dL and less than 130 mg / dL. The method of claim 1, wherein the LDL-cholesterol level of the subject group is at least 130 mg / dL. The method of claim 1, wherein the non-HDL-cholesterol level of the subject group is at least 130 mg / dL. The method of claim 1, wherein the LDL-cholesterol level of the subject group is at least 100 mg / dL and the triglyceride level is at least 200 mg / dL. The method of claim 1, wherein the non-HDL-cholesterol level of the subject group is at least 130 mg / dL and the triglyceride level is at least 200 mg / dL. The method of claim 1 wherein the omega-3 fatty acid is present at a concentration of at least 40% by weight relative to the total fatty acid content of the composition. The method of claim 1, wherein the omega-3 fatty acid is present at a concentration of at least 80% by weight relative to the total fatty acid content of the composition. The method of claim 1 wherein the omega-3 fatty acid comprises at least 80% by weight EPA and DHA compared to the total fatty acid content of the composition. The method of claim 1, wherein the omega-3 fatty acid comprises from about 40% to about 55% by weight of EPA compared to the total fatty acid content of the composition. The method of claim 1, wherein the omega-3 fatty acid comprises from about 30% to about 60% by weight of DHA compared to the total fatty acid content of the composition. The method of claim 1, wherein the omega-3 fatty acids comprise omega-3 polyunsaturated long chain fatty acids, esters of omega-3 fatty acids and glycerol, esters of omega-3 fatty acids and primary, secondary or tertiary alcohols or mixtures thereof How to do. The method of claim 1 wherein the omega-3 fatty acid comprises EPA and DHA in a ratio of EPA: DHA 2: 1 to 1: 2. The method of claim 1, wherein the omega-3 fatty acid is administered separately from the administration of the dyslipidemia. The method of claim 1, wherein the omega-3 fatty acid is administered simultaneously with the administration of the dyslipidemia. The method of claim 1, wherein the omega-3 fatty acid and the dyslipidemic agent are administered in a concurrent treatment regimen. The method of claim 1, wherein the omega-3 fatty acid and the dyslipidemic agent are administered together in a unit dosage form. The method of claim 1, wherein the basal triglyceride level of the subject group is 200 to 499 mg / dl. The method of claim 1, wherein the LDL-C level does not increase.